Natural Compounds, Optimal Combination of Brusatol and Polydatin Promote Anti-Tumor Effect in Breast Cancer by Targeting Nrf2 Signaling Pathway

by Selleckchem | Jul 07 2023

Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genes Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment.

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Triple-negative breast cancer (TNBC) is a subtype of breast cancer known for its aggressive nature and poor prognosis compared to other breast cancer subtypes. Current treatment options for TNBC often involve small-molecule drugs and inhibitors, but they can be associated with poor patient tolerance, high doses, frequent administration, and toxic side effects. Therefore, there is a need for more efficient and less toxic treatment strategies for TNBC.

One potential target in TNBC therapy is Nrf2, which is a crucial antioxidant transcription factor. Elevated Nrf2 expression is often observed in TNBC and promotes tumor progression. Targeting Nrf2 has shown promise in breast cancer treatment. In this context, a study investigated the combination of two compounds, brusatol (BRU) and polydatin (PD), for their effects on TNBC cells.

The study focused on two TNBC cell lines, MDA-MB-231 cells and SUM159 cells. The researchers found that the combination of BRU and PD significantly inhibited cell proliferation in vitro. Additionally, this combination downregulated the expression of Nrf2 protein as well as the expression of downstream target genes such as Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1). These genes are associated with Nrf2 activity and are involved in antioxidant defense.

Moreover, the BRU and PD combination also promoted the accumulation of reactive oxygen species (ROS) within the cells. ROS are highly reactive molecules that can induce cellular damage, including DNA damage, and can further enhance the anti-tumor effect. By increasing ROS levels, the combination treatment potentially induced cytotoxicity specifically in TNBC cells.

Furthermore, the researchers conducted in vivo experiments and observed that by reducing the dosage of the drug three times, they could achieve significant inhibition of tumor cell growth. Importantly, this dosage reduction helped to mitigate toxic side effects associated with the treatment, making it a more viable and clinically applicable approach for TNBC treatment.

In summary, the study demonstrated that the combination of BRU and PD effectively inhibited cell proliferation, downregulated Nrf2 and its downstream target genes, promoted ROS accumulation, and reduced tumor cell growth in TNBC. The ability to reduce the drug dosage while maintaining therapeutic efficacy and minimizing toxic side effects suggests that this treatment strategy holds promise for clinical application in TNBC therapy. However, further research and clinical trials are needed to validate these findings and establish the safety and effectiveness of this treatment approach in human patients.